The present invention refers to novel 6-(4-phenyl-butoxy)hexylamine derivatives of the general formula (I) as well as to a process for the obtention thereof. The invention also refers to a process for the obtention of Salmeterol from said novel derivatives.
The novel 6-(4-phenylbutoxy)hexylamine derivatives are represented by the general formula (I): 
wherein:
R1 is CHO or CHOR3OR4, where R3 and R4 independently are C1-C6 alkyl, aralkyl or they form 5 or 6 membered cyclic acetals; and
R2 is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
Said derivatives are useful as intermediates in the synthesis of Salmeterol.
It is known the use of Salmeterol in the therapeutical field and specially for the treatment of asthma because of its properties as a bronchodilator. Several references may be found in the literature which describe processes for the obtention of Salmeterol.
Thus, Patent FR 2545482 discloses the following procedures for the obtention of Salmeterol:
By alkylation of an amine of the general formula 1 with an alkylating agent of the general formula 2: 
where R3, R5 and R6 each represent a hydrogen atom or a protecting group, and L a leaving group as chlorine, bromine, iodine, mehanesufonyloxy or p-toluenesulfonyloxy and further removal of the eventually present protecting groups.
Alternatively, alkylation may be carried out by reductive amination of aldehyde 3 with amine 1 (R3=H or a group convertible into H under the reaction conditions). 
By reduction of a compound of the general formula 4: 
wherein R5 is a hydrogen atom or a protecting group, and at least one of the X, X1, X2, X3 and X4 radicals is a reducible group; and further removal of the eventually present protecting groups.
Suitable reducible groups are:
X : COOH or COOR7 (where R7 is H, alkyl, aryl or aralkyl), and CHO.
X1: Cxe2x95x90O.
X2: CH2NY (where Y is convertible into H by hydrogenation), CHxe2x95x90N and CONH.
X3: CO(CH2)5, CHxe2x95x90CHxe2x80x94(CH2)4, CH2CHxe2x95x90CH(CH2)3, etc.
X2xe2x80x94X3: CH2Nxe2x95x90CH (CH2)5.
X4: CHxe2x95x90CH(CH2 )2, CH2CHxe2x95x90CHCH2, etc.
By reaction of epoxide 5 or halohydrine 6 with the amine 7: 
where Y1 is H or a group convertible into hydrogen by hydrogenation; and further removal of the eventually present protecting groups.
On the other hand, Patent WO 9824753 discloses an asymmetric synthesis of amine 10 and its application to the synthesis of optically active Salmeterol.
The asymmetric addition of nitromethane to the aldehyde 8 affords the optically active nitroderivative 9, the reduction of which leads to amine 10. 
where R1 and R2 are suitable protecting groups.
However, these procedures described in the prior art present some drawbacks. The starting compounds are highly functionalized low-molecular weight intermediates, whereby its obtention involves considerably complex reactions, specially at industrial level, mainly due to the formation of undesirable byproducts which, moreover, decrease the yield of the reaction.
Thus, for example, the obtention of said compound 1 (GB 1200886) comprises many steps, among them, a bromination reaction and a chloromethylation, with the ensuing possibility of formation of dibrominated derivatives and isomers, respectively.
On the other hand, halohydrine 6 is a very slightly stable compound and it is difficult to isolate due to its tendency to convert into epoxide 5 under basic conditions. Reactions for obtention of epoxides are neither simple, the use of epoxide 5 also presenting the additional drawback that the obtention of Salmeterol is effected by opening of the epoxide, which reaction is little advisable because of the obtention of many byproducts (Randall et al., Tetrahedron Letters, (1986), 2451-2454).
The present invention provides novel 6-(4-phenylbutoxy)hexylamine derivatives which are useful as starting compounds in a new procedure of obtention of Salmeterol. Said new derivatives are easily obtained from industrially available compounds by means of simple reactions such as hydrolysis or alkylation of alcohols or amines.
The present invention refers to novel 6-(4-phenylbutoxy)hexylamine derivatives of the general formula (I): 
wherein:
R1 is CHO or CHOR3OR4, where R3 and R4 independently are C1-C6 alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals; and
R2 is H, benzyl or an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
When R1 is CHO, R2 preferably is alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group.
Preferably, R2 is tert-butoxycarbonyl, benzyloxycarbonyl or ethoxycarbonyl, acetyl, benzoyl or trifluoroacetyl; and R3 and R4 independently are methyl, ethyl, benzyl, or they form 1,2-dioxolanes or 1,3-dioxanes.
It is also an object of the present invention a process for the obtention of said 6-(4-phenylbutoxy)hexylamine derivative compounds. Said process is outlined in Scheme I below. 
(R1xe2x95x90CHO, R2=alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group)
where:
R3 and R4 have the same meaning as described above;
Z1 an Z2 are each different and the same as L or NHR2, L being a leaving group such as chlorine, bromine, iodine, methanesufonyloxy or p-toluenesulfonyloxy, preferably bromine; and R2 is H or benzyl.
The process of obtention of said 6-(4-phenylbutoxy)hexylamine derivatives of the general formula (I) is carried out according to the following steps:
(i) Alkylation of an amine by reaction of a compound of the formula (11) with a compound of the formula (12) to yield a compound of the formula (I), with R1=CHOR3OR4, R2=H or benzyl: 
wherein:
R3 and R4 independently are C1-C6 alkyl, aralkyl, or they form 5 or 6 membered cyclic acetals;
Z1 and Z2 are each different and the same as L or NHR2, where L is a leaving group such as chlorine, bromine, dine, methanesulfonyloxy or p-toluenesulfonyloxy; and R2 H or benzyl;
in an inert solvent in the presence of an organic o organic base at a temperature ranging from 25xc2x0 C. to 110xc2x0 C., preferably from 80xc2x0 C. to 100xc2x0 C., to yield the compound of the general formula (I): 
wherein R1=CHOR3OR4 and R3=H or benzyl.
The inert solvent may be a high boiling-point aprotic solvent such as, for example, N,N-dimethylformamide, N-methylpirrolidone or dimethylsulfoxide, an halogenated solvent such as methylene chloride or chloroform, an ether such as tetrahydrofuran or dioxane, or an aromatic hydrocarbon such as benzene, toluene or xylene.
The organic base may be a tertiary amine such as, for example, triethylamine or diisopropylethylamine, an aromatic amine such as N,N-dimethylaniline, or a heterocyclic amine such as pyridine. The inorganic base may be a carbonate or a bicarbonate.
(ii) Protection of the amino group of a compound (I) obtained in step (i) with a suitable reagent, prior to hydrogenation when R2 is benzyl, which leads to the obtention of compounds of the formula (I), with R1=CHOR3OR4, R2 alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group.
Referring to compounds of the formula (I) (when R1=CHCOR3OR4, R2=alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group), R2, R3 and R4 must be chosen so that it should exist the possibility of removing R3 and R4 without affecting R2.
Protection of the amino group with the alkyloxycarbonyl, aryloxycarbonyl and aralkyloxycarbonyl residues is carried out by reaction of a compound of the formula (I), wherein R1=CHOR3OR4, R2=H, with a chloroformate such as, for example, ethyl chloroformate, tert-butyl chloroformate or benzyl chloroformate; a dicarbonate such as di-tert-butyl dicarbonate or dibenzyl dicarbonate; or specific reagents such as N-(benzyloxycarbonyl)succinimide. Protection with acyl groups is performed with conventional reagents such as acid chlorides or anhydrides.
The protection reaction is accomplished in an inert solvent, eventually in the presence of an organic or inorganic base, at a temperature ranging from 0xc2x0 C. to 50xc2x0 C.
The inert solvent may be a ketone as, for example, acetone; a halogenated derivative such as methylene chloride or chloroform; an ester such as, for example, ethyl acetate; an ether such as tetrahydrofuran or dioxane; or a high boiling- point solvent as N,N-dimethylacetamide or N,N-dimethylformamide.
The bases used for this reaction may be the same than the above mentioned ones when referring to step (i).
(iii) Conversion of the compound of the formula (I), obtained in step (ii), into the corresponding aldehyde by hydrolysis, transacetalization or hydrogenolysis of the acetal group, taking into account, when choosing the procedure, the compatibility with group R2. Such conversion leads to the obtention of compounds of the formula (I), whit R1=CHO, R2=alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, or an acyl group.
Hydrolysis is carried out in an organic solvent, in the presence of an at least stoichiometric amount of water and of an organic or inorganic acid such as hydrochloric, sulfuric, methanesulfonic, p-toluenesulfonic or trifluoroacetic acid, at a temperature preferably ranging from 15xc2x0 C. to 50xc2x0 C.
The solvent may be a ketone as acetone, an alcohol as methanol, ethanol or isopropanol, an amide as N,N-dimethylformamide or N,N-dimethylacetamide, etc.
Transacetalization is accomplished in the presence of a ketone such as, for example, acetone which at the same time acts as a solvent, and of an organic or inorganic acid as methanesulfonic, p-toluenesulfonic, hydrogen chloride or sulfuric, at a temperature preferably ranging from 15xc2x0 C. to 50xc2x0C.
Hydrogenolysis is carried out under typical debenzylation conditions, in the presence of a catalyst in an inert solvent at a temperature ranging from 10xc2x0 C. to 50xc2x0 C. The catalyst preferably is palladium adsorbed on carbon.
The solvent may be a C1 to C4 aliphatic alcohol such as, for example, methanol, ethanol, isopropanol or butanol, an ester such as, for example, ethyl acetate, or an ether such as, for example, tetrahydrofuran.
The reaction temperature is preferably comprised between 15xc2x0 C. and 25xc2x0 C.
Compounds of the formula (I) obtained according to the above procedure are useful as intermediates in the synthesis of Salmeterol.
It is also an object of the present invention a process for the obtention of Salmeterol, or its pharmaceutically acceptable salts, from a compound of the general formula (I). Said procedure is characterized in that a reaction of an organometallic compound of the general formula (13) is carried out with a compound of the general formula (I): 
where:
R3 and R4 independently are C1-C6 alkyl, aralkyl, or they form cyclic acetals of the 1,3-dioxolane type;
M is a group containing a metal such as lithium, magnesium or copper, preferably M is Li, MgBr or MgCl; and
R1 is CHO and R2 is an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
Preferably, R3 and R4 independently are methyl, ethyl or benzyl, or they form cyclic acetals such as 2,2-dimethyl-1,3-dioxane or 2-methyl-1,3-dioxane.
Preferably, R2 is tert-butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, acetyl, benzoyl or trifluoroacetyl.
The reaction is carried out in an ether-like inert solvent, preferably ethyl ether or tetrahydrofuran at low temperatures preferably ranging from xe2x88x9240xc2x0 C. to 40xc2x0 C. and more preferably from xe2x88x9240xc2x0 C. to 10xc2x0 C.
The organometallic compound of the formula 13 may me obtained according to processes described in the literature (Effenberger, F.; Jxc3xa4ger, J., J. Org. Chem. (1977), 62, 3867-3873. Seebach, D., Neumann, H., Chem. Ber. (1974), 107, 874-853).
As shown in Scheme II, reaction of compound (I) with the organometallic 13 gives, after further hydrolysis, the alcohol 14, which, by subsequent removal of the protecting groups R2, R3 and R4, leads to Salmeterol. 
where:
R3 and R4 independently are C1-C6 alkyl, aralkyl, or they form cyclic acetals of the 1,3-dioxane type such as 2,2-dimethyl-1,3-dioxane or 2-methyl-1,3-dioxane; and
R2 is an alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or acyl group.
Isolation of alcohol 14 involves an aqueous treatment, in an acidic medium, of the crude product from the reaction.
Removal of the previously defined protecting groups R2, R3 and R4 from compound of the formula 15 leads to Salmeterol. This stage may be performed in one or several steps. The reaction conditions depend upon the nature of the different protecting groups, and it may be carried out by acid or basic hydrolysis or by hydrogenolysis according to conventional methods (see, e.g.: xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd ed., John Wiley and Sons Ed., Inc. 1991).
Salmeterol may be converted into its pharmacologically acceptable addition salts, such as hydrochloride, fumarate, maleate or xynaphoate, following conventional procedures.
Experimental